B Cell ADAM10 Controls Murine Lupus Progression through Regulation of the ICOS:ICOS Ligand Axis
B Cell ADAM10 Controls Murine Lupus Progression through Regulation of the ICOS:ICOS Ligand Axis
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DOI：
10.4049/jimmunol.1801207
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发表时间：
2019-02-01
影响因子：
4.4
通讯作者：
Martin, Rebecca K.
中科院分区：
文献类型：
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作者：
Lownik, Joseph C.;Wimberly, Jessica L.;Martin, Rebecca K.
在狼疮小鼠模型中，ICOS及其配体(ICOSL)的作用被证明对适当的体液反应和自身免疫抗体的产生都是必不可少的。在这篇文章中，我们报道了B细胞上金属蛋白酶ADAM10在调节ICOSL和ICOS中的特殊作用，在B6(mir146a-/-)小鼠体液免疫增强模型和淋巴增生性疾病模型中使用了特征良好的LPR模型。缺乏B细胞ADAM10的B6(LPR)小鼠(A10B(LPR))与对照B6(LPR)小鼠相比，结节增殖和T细胞聚集减少。此外，A10B(LPR)小鼠自身免疫抗双链DNA抗体的产生显著减少。与此相一致，我们发现这些小鼠的滤泡辅助T细胞和生发中心B细胞显著减少。我们还表明，在这个模型中，淋巴增殖与ICOS水平的升高和ICOSL水平的降低密切相关。总体而言，我们的数据不仅显示了B细胞ADAM10在控制自身免疫中的作用，而且增加了我们对自身免疫背景下ICOS和ICOSL调节的理解。
The role of ICOS and its ligand (ICOSL) have both been shown to be essential for proper humoral responses as well as autoimmune Ab development in mouse models of lupus. In this paper, we report a specific role for the metalloprotease ADAM10 on B cells in regulating both ICOSL and ICOS in a mouse model of increased humoral immunity using B6(mir146a-/-) mice and a model of lymphoproliferative disease using the well-characterized lpr model. B6(lpr) mice lacking ADAM10 on B cells (A10B(lpr)) have decreased nodal proliferation and T cell accumulation compared with control B6(lpr) mice. Additionally, A10B(lpr) mice have a drastic reduction in autoimmune anti-dsDNA Ab production. In line with this, we found a significant reduction in follicular helper T cells and germinal center B cells in these mice. We also show that lymphoproliferation in this model is closely tied to elevated ICOS levels and decreased ICOSL levels. Overall, our data not only show a role of B cell ADAM10 in control autoimmunity but also increase our understanding of the regulation of ICOS and ICOSL in the context of autoimmunity.